Project Summary Nearly half of mechanically ventilated (MV), critically ill adults develop ventilator-induced respiratory muscle weakness (particularly of the diaphragm), which impairs successful weaning from MV, often leads to re- intubation, and is associated with higher post-ICU mortality. We have recently shown that respiratory muscle weakness is associated with extubation failure in critically ill children, but we still lack crucial information on the mechanisms and timing of this weakness, its importance for ventilator weaning, and its potential prevention through promoting more physiologic levels of patient effort of breathing during MV. Diaphragm weakness is most common in patients exposed to high levels of controlled ventilation. In children, we have shown that usual care ventilator management is frequently associated with minimal patient effort of breathing. To enhance patient effort, we developed a novel computer-based approach (Real-time Effort Driven ventilator management (REDvent)), which offers systematic recommendations to reduce controlled ventilation during the acute phase of MV, and uses real-time measures to adjust supported ventilator pressures such that patient effort of breathing remains in a normal range during the ventilator weaning phase. Through a Phase I clinical trial, we demonstrated that patients managed with REDvent spent fewer days on MV than historical controls, and bedside providers could easily implement REDvent. Our central hypothesis is that REDvent use will reduce ventilator-induced respiratory muscle weakness, leading to shorter time on MV by enhancing the patient?s capacity for effective, unsupported ventilation and by facilitating MV weaning. This application proposes a Phase II controlled clinical trial that will obtain comprehensive, serial assessments of respiratory muscle strength and architecture to understand the evolution of ventilator-induced respiratory muscle weakness in critically ill children, and test whether REDvent can preserve respiratory muscle strength and reduce time on MV. Three integrated yet independent Specific Aims are proposed: SA 1 will determine the clinical impact of REDvent by examining whether REDvent use for either acute or weaning phase ventilator management results in shorter MV weaning times compared to usual care; SA 2 will use a sophisticated, multi-modal approach to obtain a comprehensive view of respiratory muscle capacity, effort, load, and architecture to quantify the importance of respiratory muscle weakness on weaning outcomes in children, and identify when this weakness develops; SA 3 seeks to determine the independent effect of patient effort of breathing on the development of respiratory muscle weakness, after controlling for known or suspected risk factors for respiratory muscle weakness. Upon completion, this study will provide important information on the pathogenesis and timing of respiratory muscle weakness during MV in children, whether this weakness can be mitigated by promoting more normal patient effort during MV via the use of REDvent; forming the basis for a larger, Phase III multi-center study, powered for key clinical outcomes such as 28-day Ventilator Free Days.